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Black Box Warning
WARNING: EMBRYO-FETAL TOXICITY
See full prescribing information for complete Boxed Warning.
IMPAVIDO may cause fetal harm. Fetal death and teratogenicity occurred in animals administered miltefosine at doses lower than the recommended human dose. Do not administer IMPAVIDO to pregnant women. Obtain a serum or urine pregnancy test in females of reproductive potential prior to prescribing IMPAVIDO. Females of reproductive potential should be advised to use effective contraception during IMPAVIDO therapy and for 5 months after therapy.
Overview
Miltefosine is an antimicrobial drug that is FDA approved for the treatment of {{{indication}}}. There is a Black Box Warning for this drug as shown here. Common adverse reactions include .
Adult Indications and Dosage
FDA-Labeled Indications and Dosage (Adult)
Indications
IMPAVIDO (miltefosine) capsules are indicated in adults and adolescents ≥12 years of age weighing ≥ 30 kg for the treatment of:
Visceral leishmaniasis caused by Leishmania donovani.
Cutaneous leishmaniasis caused by Leishmania braziliensis, Leishmania guyanensis, and Leishmania panamensis.
Mucosal leishmaniasis caused by Leishmania braziliensis.
Limitations of Use:
Leishmania species studied in clinical trials evaluating IMPAVIDO were based on epidemiologic data.
There may be geographic variation in clinical response of the same Leishmania species to IMPAVIDO.
The efficacy of IMPAVIDO in the treatment of other Leishmania species has not been evaluated.
Dosage
The treatment duration is 28 consecutive days. Administer with food to ameliorate gastrointestinal adverse reactions.
This image is provided by the National Library of Medicine.
DOSAGE FORMS AND STRENGTHS
IMPAVIDO® (miltefosine) oral capsules are opaque, red, hard gelatin capsules with “PLB” imprinted on the capsule body and “MILT 50” imprinted on the cap using a white ink. Each capsule contains 50 mg miltefosine.
Off-Label Use and Dosage (Adult)
Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Miltefosine in adult patients.
Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Miltefosine in adult patients.
Pediatric Indications and Dosage
FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Miltefosine in pediatric patients.
Off-Label Use and Dosage (Pediatric)
Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Miltefosine in pediatric patients.
Non–Guideline-Supported Use
Condition1
Dosing Information
Dosage
Condition2
There is limited information regarding Off-Label Non–Guideline-Supported Use of Miltefosine in pediatric patients.
Contraindications
Pregnancy
IMPAVIDO may cause fetal harm. IMPAVIDO is contraindicated in pregnant women. Obtain a urine or serum pregnancy test prior to prescribing IMPAVIDO.
Sjögren-Larsson-Syndrome
IMPAVIDO is contraindicated in patients who have Sjögren-Larsson-Syndrome.
Hypersensitivity
IMPAVIDO is contraindicated in patients who are hypersensitive to miltefosine or any IMPAVIDO excipients.
Warnings
WARNING: EMBRYO-FETAL TOXICITY
See full prescribing information for complete Boxed Warning.
IMPAVIDO may cause fetal harm. Fetal death and teratogenicity occurred in animals administered miltefosine at doses lower than the recommended human dose. Do not administer IMPAVIDO to pregnant women. Obtain a serum or urine pregnancy test in females of reproductive potential prior to prescribing IMPAVIDO. Females of reproductive potential should be advised to use effective contraception during IMPAVIDO therapy and for 5 months after therapy.
Embryo-Fetal Toxicity
Miltefosine may cause fetal harm. Embryo-fetal toxicity, including death and teratogenicity, was observed in animals administered miltefosine prior to mating, during early pregnancy, and during organogenesis at doses lower than the maximum recommended human dose (MRHD). Do not use IMPAVIDO in pregnant women. Obtain a urine or serum pregnancy test prior to prescribing IMPAVIDO to females of reproductive potential. Advise females of reproductive potential to use effective contraception during IMPAVIDO therapy and for 5 months after completion of therapy.
Reproductive Effects
Females
Miltefosine caused impaired fertility in rats and reversible follicular atresia and diestrus in dogs at doses approximately 1.0 and 0.2 times respectively the MRHD based on body surface area comparisons. Effects on human female fertility have not been formally studied.
Males
Miltefosine caused reduced viable sperm counts and impaired fertility in rats at doses approximately 0.4 times the MRHD. A higher dose in rats, approximately 1.0 times the MRHD, caused testicular atrophy and impaired fertility that did not fully reverse 10 weeks after drug administration ended.
Scrotal pain and decreased or absent ejaculation during therapy have been reported during IMPAVIDO therapy [see Adverse Reactions (6.2)]. The effects of IMPAVIDO on human male fertility have not been adequately studied.
Advise women and men of the animal fertility findings, and that the potential for impaired fertility with IMPAVIDO therapy in humans has not been adequately evaluated.
Renal Effects
Elevations of serum creatinine (Cr) were noted in clinical trials evaluating IMPAVIDO in the treatment of cutaneous, mucosal and visceral leishmaniasis. Monitor renal function weekly in patients receiving IMPAVIDO during therapy and for 4 weeks after end of therapy.
Hepatic Effects
Elevations in liver transaminases (ALT, AST) and bilirubin were noted in clinical trials evaluating IMPAVIDO in the treatment of visceral leishmaniasis. Monitor liver transaminases (ALT, AST) and bilirubin during therapy in patients receiving IMPAVIDO.
Gastrointestinal Effects
Vomiting and/or diarrhea commonly occur during IMPAVIDO administration and may result in volume depletion. Encourage fluid intake to avoid volume depletion.
Thrombocytopenia
Thrombocytopenia during therapy has been reported in patients treated for visceral leishmaniasis. Monitor platelet count during therapy for visceral leishmaniasis.
Absorption of Oral Contraceptives
Vomiting and/or diarrhea occurring during IMPAVIDO therapy may affect the absorption of oral contraceptives, and therefore compromise their efficacy. If vomiting and/or diarrhea occur during IMPAVIDO therapy, advise females to use additional non-hormonal or alternative method(s) of effective contraception.
Stevens-Johnson Syndrome
Stevens-Johnson syndrome has been reported during IMPAVIDO therapy.Discontinue IMPAVIDO if an exfoliative or bullous rash is noted during therapy.
Adverse Reactions
Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
Clinical Trials Experience
Visceral Leishmaniasis
One Phase 3 trial was conducted in patients ≥ 12 years of age in India. Two-hundred and ninety-nine (299) patients (211 men and 88 women) received oral IMPAVIDO at a target dose of 2.5 mg/kg/day for 28 days (50 mg capsule once daily if weight was less than 25 kg and 50 mg capsule twice daily if weight was 25 kg or greater). Patients ranged between 12 and 64 years of age. Weight ranged between 15 and 67 kg (mean weight 38.6 kg) and BMI ranged between 8.2 and 24 (mean 16.1). Ninety-nine (99) patients received 1 mg/kg/day amphotericin B deoxycholate intravenously every other day for 15 doses. A statistically significant higher percentage of men received IMPAVIDO compared to amphotericin B.
Less than 1% of patients who received IMPAVIDO died (2/299) and no patient who received amphotericin B died. Serious adverse reactions were reported in 2% of IMPAVIDO recipients (6/299) and 1% of amphotericin B recipients (1/99). Approximately 3% of patients discontinued treatment in each treatment arm due to an adverse reaction. Serious adverse reactions and adverse reactions leading to drug discontinuation that were thought to be related or possibly related to IMPAVIDO included Stevens-Johnson syndrome, melena and thrombocytopenia, arthritis and skin rash, CTCAE1 Grade 4 diarrhea (≥10 stools per day) and CTCAE Grade 4 hyperbilirubinemia (≥10x upper limit of normal ULN).
This image is provided by the National Library of Medicine.
In this study, creatinine (Cr) elevations ≥ 1.5 times above baseline occurred in approximately 10% of IMPAVIDO recipients and in 40% of amphotericin B recipients at the end of therapy. Ten percent of subjects in each arm had Cr elevations ≥1.5 times above baseline at 6 months follow up. No IMPAVIDO recipient discontinued therapy due to Cr elevation.
Elevations of transaminases during therapy occurred in up to half of IMPAVIDO recipients and up to a third of amphotericin B recipients. The elevations were mild (< 3x ULN) or moderate (3-5x ULN) in 94% and 6% respectively of IMPAVIDO-treated patients who experienced an elevation. No patient discontinued therapy due to elevations in transaminases.
At the end of therapy, 62% and 2.4% of IMPAVIDO recipients and 54% and 2% of amphotericin B recipients had platelet count < 150,000 and < 50,000 respectively.
Cutaneous Leishmaniasis
The efficacy of IMPAVIDO in the treatment of cutaneous leishmaniasis was evaluated in one placebo-controlled trial conducted in Colombia and Guatemala and in two comparative trials conducted in Bolivia and Brazil respectively. In the placebo-controlled trial, eighty-nine (89) patients ≥12 years of age received a target IMPAVIDO dose of 2.5 mg/kg/day for 28 days and forty-four (44) received placebo. In the comparative trials, one hundred and twenty (120) patients ≥12 years of age received a target IMPAVIDO dose of 2.5 mg/kg/day for 28 days and fifty eight (58) patients received 20 mg/kg/day pentavalent antimony (meglumine) parenterally for 20 days.
This image is provided by the National Library of Medicine.
This image is provided by the National Library of Medicine.
In the placebo controlled trial, 12/89 (13.4%) IMPAVIDO subjects had Cr increases of 1.5-3 times above baseline, compared to 2/44 (4.5%) placebo subjects at end of therapy. In the comparative trial, a similar percentage of subjects who received IMPAVIDO or pentavalent antimony had Cr elevations above baseline at 3 and 6 months after therapy (approximately 5%). Approximately 25% of IMPAVIDO subjects and 11% of pentavalent antimony subjects had Cr elevations 1.5-3 times above baseline at the end of therapy in the two active controlled trials. The frequency of AST and ALT increase above upper limit of normal at end of therapy was similar in IMPAVIDO and placebo recipients (approximately 5%).
The following adverse reactions have been identified during use of IMPAVIDO worldwide. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
